[SARS-CoV-2 Infection in Pregnancy and Incidence of Congenital Malformations - is there a Correlation? Analysis of 8032 Pregnancies from the CRONOS Registry]. / SARS-CoV-2-Infektion in der Schwangerschaft und Auftreten von angeborenen Fehlbildungen ­ Besteht ein Zusammenhang? Auswertung von 8032 Schwangerschaften aus dem CRONOS-Register.

BACKGROUND: Based on single case reports, the COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS) registry, sponsored by the German Society for Perinatal Medicine (DGPM), investigated the likelihood that SARS-CoV-2 infections of the mother in (early) pregnancy cause embryopathies and/or fetopathies. MATERIAL/METHODS: The CRONOS registry enrolled a total of 8032 women with confirmed SARS-CoV-2 infection during pregnancy at more than 130 participating hospitals from April 2020 to February 2023. Both maternal and fetal data were documented and the anonymized multicenter data were analyzed. RESULTS: Of 7142 fully documented pregnancies (including postnatal data), 140 showed congenital malformations. 8.57% of the mothers had had a SARS-CoV-2-infection in the 1st trimester and 36.43% in the 2nd trimester. In 66 cases with congenital malformations (47.14%), the malformation was only detected after the diagnosis of a maternal SARS-CoV-2 infection. The overall prevalence of congenital malformations in this cohort was 1.96%, compared to a prevalence of 2.39% reported in the EUROCAT (European network of population-based registries for the epidemiological surveillance of congenital anomalies) pre-pandemic registry between 2017-2019. DISCUSSION: Our multicenter data argue against a link between maternal SARS-CoV-2 infection in early pregnancy and congenital malformation.

Epidemiology of inherited epidermolysis bullosa in Germany.

BACKGROUND: Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity. OBJECTIVE: Epidemiological data from different countries have been published, but none are available from Germany. METHODS: In this population-based cross-sectional study, people living with EB in Germany were identified using the following sources: academic hospitals, diagnostic laboratories and patient organization. RESULTS: Our study indicates an overall EB incidence of 45 per million live births in Germany. With 14.23 per million live births for junctional EB, the incidence is higher than in other countries, possibly reflecting the availability of early molecular genetic diagnostics in severely affected neonates. Dystrophic EB was assessed at 15.58 cases per million live births. The relatively low incidence found for EB simplex, 14.93 per million live births, could be explained by late or missed diagnosis, but also by 33% of cases remaining not otherwise specified. Using log-linear models, we estimated a prevalence of 54 per million for all EB types, 2.44 for junctional EB, 12.16 for dystrophic EB and 28.44 per million for EB simplex. These figures are comparable to previously reported data from other countries. CONCLUSIONS: Altogether, there are at least 2000 patients with EB in the German population. These results should support national policies and pharmaceutical companies in decision-making, allow more precise planning of drug development and clinical trials, and aid patient advocacy groups in their effort to improve quality of life of people with this orphan disease.

A Causal Treatment for X-Linked Hypohidrotic Ectodermal Dysplasia: Long-Term Results of Short-Term Perinatal Ectodysplasin A1 Replacement.

X-linked hypohidrotic ectodermal dysplasia (XLHED), caused by a genetic deficiency of ectodysplasin A1 (EDA1), is a rare developmental disorder of ectodermal derivatives such as hair, sweat glands, and teeth. The absence of sweat glands and perspiration can evoke life-threatening hyperthermia. As molecular genetic findings are not always conclusive, the concentrations of circulating EDA1 may help to distinguish between total and partial EDA1 deficiencies. We previously treated nine male patients with obvious signs of XLHED with a recombinant EDA1 replacement protein, Fc-EDA, either shortly after birth (n = 3) or by prenatal administration in gestational week 26 and beyond (n = 6). Here, we present the long-term follow-up for up to six years. In patients who had received Fc-EDA after birth, neither sweat glands nor sweating ability were detected at the age of 12-60 months. In contrast, prenatal EDA1 replacement resulted in ample sweat gland development and pilocarpine-inducible sweating in all treated subjects, who also attained more permanent teeth than their untreated affected relatives. Normal perspiration has persisted for six years in the two oldest boys treated repeatedly with Fc-EDA in utero. When they had a sauna, adequate thermoregulation was evidenced. Lower sweat production after single prenatal dosing may indicate a dose-response relationship. The absence of circulating EDA1 in five prenatally treated subjects proved that these children would have been unable to perspire if they had been left untreated. The sixth infant was shown to produce an EDA1 molecule that, albeit interacting with its cognate receptor, cannot activate EDA1 signaling. In conclusion, a causal treatment of XLHED before birth is feasible.

A surrogate cell-based SARS-CoV-2 spike blocking assay.

To monitor infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and successful vaccination against coronavirus disease 2019 (COVID-19), the kinetics of neutralizing or blocking anti-SARS-CoV-2 antibody titers need to be assessed. Here, we report the development of a quick and inexpensive surrogate SARS-CoV-2 blocking assay (SUBA) using immobilized recombinant human angiotensin-converting enzyme 2 (hACE2) and human cells expressing the native form of surface SARS-CoV-2 spike protein. Spike protein-expressing cells bound to hACE2 in the absence or presence of blocking antibodies were quantified by measuring the optical density of cell-associated crystal violet in a spectrophotometer. The advantages are that SUBA is a fast and inexpensive assay, which does not require biosafety level 2- or 3-approved laboratories. Most importantly, SUBA detects blocking antibodies against the native trimeric cell-bound SARS-CoV-2 spike protein and can be rapidly adjusted to quickly pre-screen already approved therapeutic antibodies or sera from vaccinated individuals for their ACE2 blocking activities against any emerging SARS-CoV-2 variants.

Unbound Corneocyte Lipid Envelopes in 12R-Lipoxygenase Deficiency Support a Specific Role in Lipid-Protein Cross-Linking.

Loss-of-function mutations in arachidonate lipoxygenase 12B (ALOX12B) are an important cause of autosomal recessive congenital ichthyosis (ARCI). 12R-lipoxygenase (12R-LOX), the protein product of ALOX12B, has been proposed to covalently bind the corneocyte lipid envelope (CLE) to the proteinaceous corneocyte envelope, thereby providing a scaffold for the assembly of barrier-providing, mature lipid lamellae. To test this hypothesis, an in-depth ultrastructural examination of CLEs was performed in ALOX12B-/- human and Alox12b-/- mouse epidermis, extracting samples with pyridine to distinguish covalently attached CLEs from unbound (ie, noncovalently bound) CLEs. ALOX12B--/- stratum corneum contained abundant pyridine-extractable (ie, unbound) CLEs, compared with normal stratum corneum. These unbound CLEs were associated with defective post-secretory lipid processing, and were specific to 12R-LOX deficiency, because they were not observed with deficiency of the related ARCI-associated proteins, patatin-like phospholipase 1 (Pnpla1) or abhydrolase domain containing 5 (Abhd5). These results suggest that 12R-LOX contributes specifically to CLE-corneocyte envelope cross-linking, which appears to be a prerequisite for post-secretory lipid processing, and provide insights into the pathogenesis of 12R-LOX deficiency in this subtype of ARCI, as well as other conditions that display a defective CLE.

Maternal SARS-CoV-2 infection during pregnancy: possible impact on the infant.

The risk and potential consequences of mother-to-child transmission of severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) during pregnancy are still a matter of debate. We studied the impact of SARS-CoV-2 infection on 56 complete households, including 27 newborns whose mothers were pregnant when exposed to the virus. Two PCR-confirmed perinatal SARS-CoV-2 transmissions with mild symptoms in affected neonates were recorded. In addition, we observed a severe eye malformation (unilateral microphthalmia, optic nerve hypoplasia, and congenital retinopathy) associated with maternal SARS-CoV-2 infection in weeks 5 and 6 of embryonic development. This embryopathy could not be explained by other infectious agents, genetic factors, drug use, or maternal disease during pregnancy. Eight other women with a history of SARS-CoV-2 infection prior to gestational week 12, however, delivered healthy infants.Conclusion: The repeated occurrence of mother-to-child transmission in our cohort with risks that remain incompletely understood, such as long-term effects and the possibility of an embryopathy, should sensitize researchers and stimulate further studies as well as support COVID-19 vaccination recommendations for pregnant women. Trial registration number: NCT04741412. Date of registration: November 18, 2020 What is Known: •Materno-fetal transmission of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) during pregnancy has rarely been reported so far, but was demonstrated in isolated cases. What is New: •In a study of complete households with documented SARS-CoV-2 infection, including a cohort of pregnant women, we observed perinatal coronavirus transmission at a higher frequency than expected. •We also describe a newborn boy with an eye malformation reminiscent of rubella embryopathy but associated with early gestation SARS-CoV-2 infection of his mother. •A coronavirus-related embryopathy, reported here for the first time, is a finding that requires further investigation.

Ectodysplasin A1 Deficiency Leads to Osteopetrosis-like Changes in Bones of the Skull Associated with Diminished Osteoclastic Activity.

Pathogenic variants of the gene Eda cause X-linked hypohidrotic ectodermal dysplasia (XLHED), which is characterized by structural abnormalities or lack of ectodermal appendages. Signs of dysplasia are not restricted to derivatives of the ectodermal layer, but mesodermal abnormalities, such as craniofacial dysmorphism, are also frequently observed, suggesting close reciprocal interactions between the ectoderm and mesoderm; however, a causal link has remained unsubstantiated. We investigated the functional impact of defective ectodysplasin A1 (Eda1) signaling on postnatal bone homeostasis in Eda1-deficient Tabby mice. Interestingly, Eda1 was detected in wild-type mouse calvariae throughout postnatal lifetime. In calvariae, bone-lining Osterix (Osx)+ osteoblasts stained positive for Eda1, and osteoclasts were revealed as Eda receptor (Edar)-positive. Moreover, adult Eda1-deficient calvarial bone showed osteopetrosis-like changes with significantly diminished marrow space, which was maintained during adulthood. Concomitantly with osteopetrosis-like changes, Tabby calvarial bone and Tabby bone marrow-derived osteoclasts had far less osteoclastic activity-associated co-enzymes including cathepsin K, Mmp9, Trap, and Tcirg1 (V-type proton ATPase a3 subunit) compared with wild-type calvariae in vivo or osteoclasts in vitro, indicating that Eda1 deficiency may affect the activity of osteoclasts. Finally, we confirmed that nuclear Nfatc1-positive osteoclasts were strongly diminished during mature osteoclastic differentiation under M-CSF and RANKL in the Tabby model, while Fc-EDA treatment of Tabby-derived osteoclasts significantly increased nuclear translocation of Nfatc1. Furthermore, we identified enhanced Nfatc1 and NF-κB transcriptional activity following Fc-EDA treatment in vitro using luciferase assays. Overall, the results indicate that diminished expressions of osteoclastic activity-associated co-enzymes may lead to disturbed bone homeostasis in Tabby calvariae postnatally.

Deficiency of Fhl2 leads to delayed neuronal cell migration and premature astrocyte differentiation.

The four and a half LIM domains protein 2 (Fhl2) is an adaptor protein capable of mediating protein-protein interactions. Here, we report for the first time phenotypic changes in the brain of Fhl2-deficient mice. We showed that Fhl2 is expressed in neural stem cells, precursors and mature cells of neuronal lineage. Moreover, Fhl2 deficiency leads to delayed neuroblast migration in vivo, premature astroglial differentiation of neural stem cells (NSCs) in vitro, and a gliosis-like accumulation of glial fibrillary acidic protein (GFAP)-positive astrocytes in vivo that substantially increases with age. Collectively, Fhl2-deficiency in the brain interrupts the maintenance and the balanced differentiation of adult NSCs, resulting in preferentially glial differentiation and early exhaustion of the NSC pool required for adult neurogenesis.

Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia.

Genetic deficiency of ectodysplasin A (EDA) causes X-linked hypohidrotic ectodermal dysplasia (XLHED), in which the development of sweat glands is irreversibly impaired, an condition that can lead to life-threatening hyperthermia. We observed normal development of mouse fetuses with Eda mutations after they had been exposed in utero to a recombinant protein that includes the receptor-binding domain of EDA. We administered this protein intraamniotically to two affected human twins at gestational weeks 26 and 31 and to a single affected human fetus at gestational week 26; the infants, born in week 33 (twins) and week 39 (singleton), were able to sweat normally, and XLHED-related illness had not developed by 14 to 22 months of age. (Funded by Edimer Pharmaceuticals and others.).

T Cell Impairment Is Predictive for a Severe Clinical Course in NEMO Deficiency.

PURPOSE: NEMO-deficient patients present with variable degrees of immunodeficiency. Accordingly, treatment ranges from antibiotic prophylaxis and/or IgG-substitution to allogenic hematopoietic stem cell transplantation (HSCT). The correct estimation of the immunodeficiency is essential to avoid over- as well as under-treatment. We compare the immunological phenotype of a NEMO-deficient patient with a newly-described splice site mutation that causes truncation of the NEMO zinc-finger (ZF) domain and a severe clinical course with the immunological phenotype of three NEMO-deficient patients with missense mutations and milder clinical courses and all previously published patients. METHODS: Lymphocyte subsets, proliferation, and intracellular NEMO-expression were assessed by FACS. NF-κB signal transduction was determined by measuring IκBα-degradation and the production of cytokines upon stimulation with TNF-α, IL-1ß, and TLR-agonists in immortalized fibroblasts and whole blood, respectively. RESULTS: The patient with truncated ZF-domain of NEMO showed low levels of IgM and IgG, reduced class-switched memory B cells, almost complete skewing towards naïve CD45RA+ T cells, impaired T cell proliferation as well as cytokine production upon stimulation with TNF-α, IL-1ß, and TLR-agonists. He suffered from severe infections (sepsis, pneumonia, osteomyelitis) during infancy. In contrast, three patients with missense mutations in IKBKG presented neither skewing of T cells towards naïvety nor impaired T cell proliferation. They are stable on prophylactic IgG-substitution or even off any prophylactic treatment. CONCLUSION: The loss of the ZF-domain and the impaired T cell proliferation accompanied by almost complete persistence of naïve T cells despite severe infections are suggestive for a profound immunodeficiency. Allogenic HSCT should be considered early for these patients before chronic sequelae occur.

Safety and immunogenicity of Fc-EDA, a recombinant ectodysplasin A1 replacement protein, in human subjects.

In X-linked hypohidrotic ectodermal dysplasia, the most frequent ectodermal dysplasia, an inherited deficiency of the signalling protein ectodysplasin A1 (EDA1) impairs the development of the skin and its appendages, various eccrine glands, and dentition. The severe hypohidrosis common to X-linked hypohidrotic ectodermal dysplasia patients may lead to life-threatening hyperthermia, especially during hot weather or febrile illness. Fc-EDA, an EDA1 replacement protein known to prevent the disease in newborn animals, was tested in 2 clinical trials (human adults and neonates) and additionally administered under compassionate use to 3 infants in utero. The data support the safety of Fc-EDA and efficacy if applied prenatally. Anti-drug antibodies were detected after intravenous administration in adult males and nonpregnant females, but not in pregnant women when Fc-EDA was delivered intra-amniotically. Most importantly, there was no detectable immune response to the investigational drug in neonates treated by intravenous infusions and in infants who had received Fc-EDA in utero. In conclusion, the safety profile of this drug encourages further development of prenatal EDA1 replacement therapy.

Prenatal Treatment of X-Linked Hypohidrotic Ectodermal Dysplasia using Recombinant Ectodysplasin in a Canine Model.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by defects in the EDA gene that inactivate the function of ectodysplasin A1 (EDA1). This leads to abnormal development of eccrine glands, hair follicles, and teeth, and to frequent respiratory infections. Previous studies in the naturally occurring dog model demonstrated partial prevention of the XLHED phenotype by postnatal administration of recombinant EDA1. The results suggested that a single or two temporally spaced injections of EDI200 prenatally might improve the clinical outcome in the dog model. Fetuses received ultrasound-guided EDI200 intra-amniotically at gestational days 32 and 45, or 45 or 55 alone (of a 65-day pregnancy). Growth rates, lacrimation, hair growth, meibomian glands, sweating, dentition, and mucociliary clearance were compared in treated and untreated XLHED-affected dogs, and in heterozygous and wild-type control dogs. Improved phenotypic outcomes were noted in the earlier and more frequently treated animals. All animals treated prenatally showed positive responses compared with untreated dogs with XLHED, most notably in the transfer of moisture through paw pads, suggesting improved onset of sweating ability and restored meibomian gland development. These results exemplify the feasibility of ultrasound-guided intra-amniotic injections for the treatment of developmental disorders, with improved formation of specific EDA1-dependent structures in dogs with XLHED.

Variants of the ectodysplasin A1 receptor gene underlying homozygous cases of autosomal recessive hypohidrotic ectodermal dysplasia.

Hypohidrotic ectodermal dysplasia (HED) is a rare genetic condition resulting from defective development of ectodermal derivatives, such as hair, teeth, and sweat glands. Autosomal recessive (AR) forms of HED may be caused by pathogenic variants of the ectodysplasin A1 receptor (EDAR) gene that encodes a receptor involved in the NF-κB signaling pathway. Here, we describe three cases of AR-HED in families of Turkish, Austrian, and German-American origin (with or without known consanguinity). In these cases, two out-of-frame deletions and a pathogenic missense variant of EDAR were found to be disease-causing due to reduced availability of the respective messenger RNA or impaired interaction of the encoded protein with its binding partner leading to diminished signal transduction. The same missense variant, c.1258C>T (p.Arg420Trp), has actually been reported to be restricted to the Icelandic population and to be associated with non-syndromic tooth agenesis but not HED. As our patient has no known relationship to Icelandic individuals and displays a rather severe HED phenotype, we suggest that EDAR-Arg420Trp is a more widespread variant, possibly with variable clinical expressivity.

Ectodermal dysplasias: Classification and organization by phenotype, genotype and molecular pathway.

An international advisory group met at the National Institutes of Health in Bethesda, Maryland in 2017, to discuss a new classification system for the ectodermal dysplasias (EDs) that would integrate both clinical and molecular information. We propose the following, a working definition of the EDs building on previous classification systems and incorporating current approaches to diagnosis: EDs are genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. Genetic variations in genes known to be associated with EDs that affect only one derivative of the ectoderm (attenuated phenotype) will be grouped as non-syndromic traits of the causative gene (e.g., non-syndromic hypodontia or missing teeth associated with pathogenic variants of EDA "ectodysplasin"). Information for categorization and cataloging includes the phenotypic features, Online Mendelian Inheritance in Man number, mode of inheritance, genetic alteration, major developmental pathways involved (e.g., EDA, WNT "wingless-type," TP63 "tumor protein p63") or the components of complex molecular structures (e.g., connexins, keratins, cadherins).

Attenuation of Severe Generalized Junctional Epidermolysis Bullosa by Systemic Treatment with Gentamicin.

Severe generalized junctional epidermolysis bullosa (JEB), a lethal genodermatosis, is mainly caused by premature termination codons (PTCs) in one of the three genes encoding the anchoring protein laminin-332. Only symptomatic treatment has been established; overcoming PTCs by aminoglycosides may represent an interesting alternative. This retrospective study aimed at assessing for the first time the clinical effects of systemic gentamicin application in infants with severe generalized JEB. Five patients, homozygous or compound-heterozygous for PTCs in the gene LAMB3, were treated with gentamicin which was administered intravenously or by intramuscular injection at doses of 7.5 mg/kg/d for three weeks. Skin biopsies were investigated by immunofluorescence analyses. Clinical effects of the medication were recorded with a parent questionnaire and by assessing weight-for-age charts. Gentamicin application was well tolerated, long hospitalization was not required. Low levels of laminin-332 could be detected in a skin sample obtained after treatment. Gentamicin had a positive impact on skin fragility and daily life in four patients but did not influence weight gain and failed to reverse the lethal course of the disease. Gentamicin injections should be considered regularly in cases of severe generalized JEB caused by PTCs as they may attenuate JEB symptoms without impeding quality of life.

Reliability of prenatal detection of X-linked hypohidrotic ectodermal dysplasia by tooth germ sonography.

OBJECTIVE: In X-linked hypohidrotic ectodermal dysplasia (XLHED), dysfunction of ectodysplasin A1 (EDA1) due to EDA mutations results in malformation of hair, teeth, and sweat glands. Hypohidrosis, which can cause life-threatening hyperthermia, is amenable to intrauterine therapy with recombinant EDA1. This study aimed at evaluating tooth germ sonography as a noninvasive means to identify affected fetuses in pregnant carrier women. METHODS: Sonography, performed at 10 study sites between gestational weeks 18 and 28, led to the diagnosis of XLHED if fewer than six tooth germs were detected in mandible or maxilla. The assessment was verified postnatally by EDA sequencing and/or clinical findings. Estimated fetal weights and postnatal weight gain of boys with XLHED were assessed using appropriate growth charts. RESULTS: In 19 of 38 sonographic examinations (23 male and 13 female fetuses), XLHED was detected prenatally. The prenatal diagnosis proved to be correct in 37 cases; one affected male fetus was missed. Specificity and positive predictive value were both 100%. Tooth counts obtained by clinical examination corresponded well with findings on panoramic radiographs. We observed no weight deficits of subjects with XLHED in utero but occasionally during infancy. CONCLUSION: Tooth germ sonography is highly specific and reliable in detecting XLHED prenatally.

Attenuation of Mammary Gland Dysplasia and Feeding Difficulties in Tabby Mice by Fetal Therapy.

Hypohidrotic ectodermal dysplasias (HED) are hereditary differentiation disorders of multiple ectodermal structures including the mammary gland. The X-linked form of HED (XLHED) is caused by a lack of the secreted signaling molecule ectodysplasin A1 (EDA1) which is encoded by the gene EDA and belongs to the tumor necrosis factor (TNF) superfamily. Although male patients (hemizygous) are usually more severely affected by XLHED, heterozygous female carriers of an EDA mutation may also suffer from a variety of symptoms, in particular from abnormal development of their breasts. In Tabby mice, a well-studied animal model of XLHED, EDA1 is absent. We investigated the effects of prenatal administration of Fc-EDA, a recombinant EDA1 replacement protein, on mammary gland development in female Tabby mice. Intra-amniotic delivery of Fc-EDA to fetal animals resulted later in improved breastfeeding and thus promoted the growth of their offspring. In detail, such treatment led to a normalization of the nipple shape (protrusion, tapering) that facilitated sucking. Mammary glands of treated female Tabby mice also showed internal changes, including enhanced branching morphogenesis and ductal elongation. Our findings indicate that EDA receptor stimulation during development has a stable impact on later stages of mammary gland differentiation, including lactation, but also show that intra-amniotic administration of an EDA1 replacement protein to fetal Tabby mice partially corrects the mammary gland phenotype in female adult animals.

Sweating ability of patients with p63-associated syndromes.

Sweating deficiency has been reported to represent a cardinal symptom of ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome and ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome, two rare p63-associated disorders. According to online resources, hypohidrosis may lead to most life-threatening complications in affected patients. Thus, counseling on the prevention of hyperthermia would be indispensable in case of such syndromes, although detailed information on this issue is missing in the literature. We investigated 14 individuals with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome (age range 2-48 years) and 9 individuals with ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome (0.5-60 years of age) by confocal laser scanning microscopy to determine their palmar sweat duct density and by quantification of pilocarpine-induced sweating. Genotype-phenotype correlations were assessed. In 12 of 23 patients (52%), a normal amount of sweat ducts was detected. These individuals (9 with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome, 3 with ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome) produced sufficient sweat volumes (≥ 20 µl) in response to pilocarpine. All other patients had clearly reduced sweating ability and fewer sweat glands, but no anhidrosis. Alteration of a specific proline residue (Pro590) of p63 was consistently linked to impaired perspiration.Conclusion: Hypohidrosis in p63-associated syndromes is less common and potentially less severe than previously thought and may be attributable to certain genotypes. What is Known: • Hypohidrosis which has been listed as a cardinal symptom of AEC and EEC syndromes may lead to life-threatening hyperthermia. What is New: • Patients with EEC and AEC syndromes often can sweat normally. • Hypohidrosis seems to be attributed to certain TP63 genotypes.

Automatic recognition of the XLHED phenotype from facial images.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a genetic disorder that affects ectodermal structures and presents with a characteristic facial appearance. The ability of automated facial recognition technology to detect the phenotype from images was assessed . In Phase 1 of this study we examined if the age of male patients affected the technology's recognition. In Phase 2 we investigated how well the technology discriminated affected males cases from female carriers and from individuals with other ectodermal dysplasia syndromes. The system detected XLHED to be the most likely diagnosis in all genetically confirmed affected male patients of all ages, and in 55% of heterozygous females. Interestingly, patients with other ED syndromes were also detected by the XLHED-targeted analysis, consistent with shared developmental features. Thus the automated facial recognition system represents a promising non-invasive technology to screen patients at all ages for a possible diagnosis of ectodermal dysplasia, with greatest sensitivity and specificity for males affected with XLHED.